DK2982673T3 - PROCEDURE FOR PREPARING 5-CHLORMETHYLPYRIDINE-2,3-DICARBOXYLYAIC ANHYRIDE - Google Patents
PROCEDURE FOR PREPARING 5-CHLORMETHYLPYRIDINE-2,3-DICARBOXYLYAIC ANHYRIDE Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/80—Acids; Esters in position 3
Description
DESCRIPTION
[0001] The invention relates to intermediates in a process for manufacturing 5-chloromethylpyridine-2,3-dicarboxylic acid anhydride, their production and further the use of these compounds in the synthesis of herbicidal 5-substituted-2-(2-imidazolin-2-yl)nicotinic acids, such as imazamox.
[0002] Derivatives of 2-(2-imidazolin-2-yl) nicotinic acids, like imazamox (2-[(RS)-4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl]-5-methoxymethyl nicotinic acid),
are useful selective herbicides which act as ALS-inhibitors and can be used in pre- and postemergence applications.
[0003] Various processes for the synthesis of these compounds are known from the literature, see e.g. EP-A 0 322 616, EP-A 0 747 360, EP-A 0 933 362 or Q. Bi et al, Modern Agrochemicals 6(2)(2007) 10-14.
[0004] Although synthesis on an industrial scale is carried out by these methods there is still room for improvement, specifically in view of economical and ecological aspects, such as overall yield improvement or the avoidance of certain solvents or reagents.
[0005] EP-A 0 322 616 discloses the preparation of 5-chloromethyl-pyridine-2,3-dicarboxylic acid anhydrides by chlorination of respective 5-methyl compounds and further conversion of these compounds to herbicidal imidazolinones.
[0006] The nitrosation of methyl-pyridines with strong bases such as butyl lithium at low temperatures is disclosed in Heterocycles 34 (1992) 1605, however, yields are very low for 3-methyl-pyridines.
[0007] US 5,334,576 and EP 0 322 616 A2 disclose the synthesis of 5-chloromethyl-2,3-pyridine dicarboxylic acid anhydride.
[0008] C. Guéret et al., J. Labelled Cpd. Radiopharm 2001, Suppl. 1 and US 5,026,859 teach that thionyl chloride can be used to convert specific hydroxymethyl pyridine compounds into the corresponding chloromethyl pyridine compound.
[0009] The task of the invention is to provide new useful intermediates for the synthesis of 5-chloromethyl-pyridine-2,3-dicarboxylic acid anhydrides.
[0010] Accordingly, in one aspect of the invention there is provided a hydroxymethyl compound of formula (VI),
wherein
Z is hydrogen or halogen; Z1 is hydrogen, halogen, cyano or nitro.
[0011] Further provided is the use of a hydroxymethyl compound (VI) according to the invention as an intermediate in the synthesis of herbicidal imidazolinones of formula (VII),
(VII) wherein Z, Z1 are as defined in formula (VI); R4 is C-1-C4 alkyl; R5 is C-1-C4 alkyl, C3-C6 cycloalkyl or R4 and R5, when taken together with the atom to which they are attached, represent a C3-C6 cycloalkyl group optionally substituted with methyl; and R6 is hydrogen or a cation.
[0012] Also provided is a process for manufacturing a hydroxymethyl compound of formula (VI), comprising the step of reducing compound (I),
(I) wherein
Z, Z1 are as defined in formula (VI); and R1, R2 are independently C-i-C-io-alkyl, with a complex metal hydride in a diluting agent at a temperature in the range of from - 20 to 60 °C and hydrolyzing the ester groups of compound (I) to obtain the hydroxymethyl compound of formula (VI).
[0013] To prepare the compound of formula VI formyl compound (I)
wherein
Z is hydrogen or halogen; Z1 is hydrogen, halogen, cyano or nitro; and R1, R2 are independently C-i-C-io-alkyl. can be reduced with a complex metal hydride to afford hydroxyl-compound (VI) as exemplified by preferred compounds (la) and (Via): /, \
(Via) (la) R1', R2 = Me, Bu [0014] Typical complex metal hydrides include compounds M1x(M2Hy) where M1 is an alkali metal, preferably Li or Na or K, M2 is a metal or metalloid, preferably B or Al, and x and y depend on the oxidation state of the metal. Preferred are LiBH4, NaBH4, KBH4, LiAIH4, NaAIH4 and KAIH4. Preferred are compounds that are relatively stable towards water and alcohols, such as NaBH4 and KBH4. A technical solution of NaBH4 in soda lye (e.g. Borol® available from Rohm and Haas, Philadelphia, USA, or Sigma Aldrich, Saint Louis, USA) is particularly preferred.
[0015] Generally 1 to 3, preferably 1 to 1.5 equivalents (based on active hydrogen) of complex metal hydride are employed per equivalent of compound (I).
[0016] The reducing agent may be used as a solid or as a solution or suspension in a suitable solvent. Such solvents are known to those skilled in the art and include, e.g. water, primary, secondary and tertiary alcohols, preferably having from 1 to 6 carbon atoms, such as isopropanol, ethanol and methanol. Preferably such solutions or suspensions are stabilized with alkali.
Employing the reducing agent as an aqueous solution or suspension is preferred. In preferred embodiments metal salts, such as LiCI or NaHS04 are added to the solution.
[0017] The reduction is generally carried out at a temperature in the range of from -20 to 60°C, preferably -10 to 40°C, in particular -5 to 25°C.
[0018] In a preferred embodiment formyl compound (I) is added to a solution/suspension of the reducing agent and the reaction mixture is stirred at the desired temperature up to the desired degree of conversion.
[0019] Working up can be achieved by conventional methods known to those skilled in the art. In order to obtain the free acid the pH value is adjusted by addition of a strong acid, such as HCI. The raw product can be isolated, e.g. by removal of the solvent and optional drying. Further purification can be effected e.g. by recrystallization or chromatographic methods. In a preferred embodiment, the raw product is not further purified, but is directly used in the following production step, simultaneous chlorination and formation of the anhydride, as exemplified with preferred compounds (Via) and (Va):
[0020] In this step chlorides and oxychlorides of sulfur and phosphorus are employed as combined chlorinating and dehydrating agents, such as SOCI2, SO2CI2, PCI3, PCI5, POCI3. Preferred are SOCI2 and POCI3 with SOCI2 being particularly preferred.
[0021] Typically 1 to 10, preferably 2 to 5, in particular 2 to 4 equivalents of chlorinating/dehydrating agent are used. Excess chlorinating agent may be recovered after completion of the reaction.
[0022] Either the chlorinating/dehydrating agent is used as a solvent or a further inert solvent is added. Suitable solvents include aromatic hydrocarbons and ethers, such as toluene, xylenes, mesitylene, chlorobenzenes, dichloromethane, 1,2-dichloroethane, diethyl ether, cycolpentyl methyl ether, methyl tert.-butyl ether (MTBE), tetrahydrofurane (THF) and dioxane, with toluene being preferred.
[0023] The reaction is typically carried out under reflux, i.e. at the boiling point of the solvent or chlorinating agent.
[0024] In a preferred embodiment hydroxyl compound (VI) is taken up in a solvent, heated to reflux, followed by addition of the chlorinating agent and maintaining under reflux until completion of the reaction.
[0025] Working up can be achieved by conventional methods known to those skilled in the art, such as removal of the solvent and drying by azeotropic distillation, e.g. with toluene.
[0026] If desired the product (V) may be further purified, however, the product thus obtained is sufficiently pure for further conversion to herbicidal imidazolinones (VII).
[0027] The compounds of formula (V) are valuable intermediates in organic synthesis. They are especially useful for conversion to herbicidal imidazolinone compounds (VII).
[0028] The use of the hydroxymethyl compound of formula (VI) is illustrated by a process for producing a herbicidal imidazolinone of formula (VII) comprising the steps of: (i) reacting a compound of formula (II),
wherein
Z is hydrogen or halogen; Z1 is hydrogen, halogen, cyano or nitro and R1, R2 are independently C-|-Cio-alkyl, with a nitrosation agent (III), r3-0-N=0 (III) wherein R3 is C-i-Cs-alkyl, in the presence of an alkali metal or alkaline earth metal alcoholate in a polar aprotic solvent at a temperature of from -45 to 40°C, to obtain an oxime compound (IV),
(iv) where Z, Z1, R1 and R2 are as in formula (I), (ii) reacting oxime compound (IV) with an aliphatic C-|-C-|o-aldehyde in the presence of an acid at a temperature in the range of from 0 to 100°C to obtain 5-formyl-pyridine-2,3-dicarboxylic acid ester (I)
wherein
Z is hydrogen or halogen; Z1 is hydrogen, halogen, cyano or nitro and R1, R2 are independently C-|-C-io-alkyl, (Hi) reducing compound (I) with a complex metal hydride in an diluting agent at a temperature in the range of from -20 to 60°C and hydrolyzing the ester groups of compound (I) to obtain hydroxyl compound (VI),
V) wherein
Z is hydrogen or halogen; z1 is hydrogen, halogen, cyano or nitro;
(VI) where Z, Z1 are as in formula (V), and (iv) treating hydroxyl compound (VI) with an chloride or oxychloride of phosphorus or sulfur to form anhydride (V). (v-a) reacting compound (V) with an 2-aminoalkane carboxamide (VIII) H2N-CR4R5-CONH2 (VIII) where R4 and R5 are as in formula (VII), or (v-b) reacting compound (V) with a 2-aminoalkane carbonitrile (IX) (v-b1), H2N-CR4R5-CN (IX) where R4 and R5 are as in formula (VII), and (v-b2) hydrolyzing the nitrile group to yield the amide (X),
(X) where Z, Z1, R4, R5, R6 are as defined in formula (VII); (vi) reacting compound (X) with CH3OM or MOH/CH3OH (where M is an alkali metal cation, preferably Na or K) followed by acidification to form the herbicidal imidazolinone (VII).
[0029] In one embodiment step (v-a) can be carried out in analogy to the procedure disclosed in example 10 of EP-A 0 322 616. Compound (V), a substituted 2-aminoalkane carboxamide (VIII) and a tertiary amine, preferably triethylamine are reacted in a polar aprotic solvent, such as acetonitrile, to yield an ammonium salt (VII), which can be acidified to an acid (VII).
[0030] In another preferred embodiment compound (V) is reacted with an 2-aminoalkane carbonitrile (IX) (step v-b1) to form a 2-carbamoyl-nicotinic acid (XI)
(XI) where R4 and R5 are defined as in fomula (VII) which is further hydrolyzed (step (v-b2)) to yield the amido compound (X).
[0031] In a preferred embodiment, compound (Va) is reacted with preferred 1-aminoalkane carbonitrile (IXa) to form preferred carbonitrile compound (Xla):
[0032] Aminonitriles (IX) are commercially available or can be prepared by methods known in the art. Generally 0.8 to 1.2 equivalents aminonitrile (IX) per equivalent of compound (V) are used, preferably 0.95 to 1.1.
[0033] The reaction is carried out in a solvent which is preferably selected from aromatic hydrocarbons, preferably toluene, mesitylenes, chlorinated aromatic hydrocarbons, such as chlorobenzene, dichlorobenzene, chlorinated hydrocarbons, such as 1,2-dichloroethane, dichloromethane, acetic acid, and mixtures thereof.
[0034] If acetic acid is not used as the main solvent, addition of 0.5 to 4 equivalents, preferably 1 to 3 equivalents (based on compound (V)), is advantageous. Further advantageous additives that improve the selectivity of the ring-opening reaction (2 versus 3 position) are listed in US 4,562,257, and comprise pyridine, 4-picoline, 2-picoline and quinoline.
[0035] The reaction is generally carried out at a temperature range of from about 40 to about 120°C, preferably of from about 60 to about 100°C. The reaction time is generally from about 1 to about 3 h.
[0036] In a preferred embodiment compound (V) is dissolved in the solvent and brought to the reaction temperature, and aminonitrile (IX) is gradually added. After completion of the reaction and cooling, nitrile compound (XI) can be isolated by standard methods.
[0037] In a preferred embodiment, however, compound (XI) is not isolated but the reaction mixture is directly used in the following hydrolyzation step of the nitrile, e.g.
[0038] In a typical procedure a slight excess (e.g. 1.1 to 1.5 equivalents based on (XI)) of a strong mineral acid, preferably sulfuric acid (preferably in a concentration of 30 to 98%) and water (e.g. 2 to 10 equivalents) are added at a temperature which is generally in the range of about 30 to 120°C, preferably 50 to 90°C. The mixture is further stirred until complete conversion. The reaction time is generally from 1 to 8 h, preferably 1 to 5 h.
[0039] Working up and isolation can be achieved by standard methods, such as precipitation from an aqueous solution (e.g. as its ammonium salt). In a preferred embodiment the reaction mixture is directly used in the following reaction step.
[0040] In a further step (vi) of the inventive process a herbicidal imidazolinone compound (VII) is prepared by conversion of amido compound (X).
[0041] In one alternative of step (vi) amido compound (X), preferably in the form of an ammonium salt (R6 is HNR3), is reacted with an alkali metal methoxide, preferably NaOCH3 in methanol in analogy to example 11 of EP 0 322 616. The resulting suspension is held at reflux until complete conversion. After cooling the mixture is acidified to obtain compound (III) either as the ammonium salt (acidification to a pH of about 4) or the free acid (acidification to pH < 2).
[0042] In a further preferred embodiment, compound (X), preferably the reaction mixture from step (v), is reacted with methanol (generally 2 to 100 equivalents based on (X)) in the presence of an aqueous base (generally 3 to 100 equivalents based on (X)), the base being preferably selected from MOH and MOCH3, where M is an alkali metal cation, preferably Na or K, particularly Na.
[0043] The reaction is carried out at a temperature in the range of from 20 to 120°C, preferably 40 to 90°C. The reaction can be carried out at atmospheric pressure or at elevated pressure, preferably the pressure forming at the desired reaction temperature. The reaction time is generally from 1 to 8 h, preferably from 1 to 5 h.
[0044] Isolation of product (VII) can be achieved by standard methods. In a preferred embodiment water is added and organic solvents are distilled off. The residue can be taken up in water and acidified, whereupon compound (VII) precipitates. After filtration the crude product can be further purified, e.g. by stirring with water or recrystallization.
[0045] The use of hydroxymethyl compound of formula (VII) is further illustrated by a process for preparing herbicidal imidazolinones of formula (VII) comprising the steps of (i)/(ii)/(iii)/(iv)/(v-b1) preparing a carbonitrile (XI) as described above and (v-b2)/(vi)) reacting compound (XI) with a base selected from MOH and MOCH3, where M is an alkali metal cation, and (aqueous) H2O2 in methanol, optionally followed by acidification
[0046] The reaction can be carried out in analogy to the procedures described in EP-AO 144 595. Described is also a process for preparing a compound of formula (XII)
where Z, Z1 are as in formula (I), comprising the steps of (i)/(ii)/(iii)/(iv) preparing a compound of formula (V) as described above, and (v-a) reacting compound (V) methanol in the presence of MOH or MOCH3, where M is an alkali metal cation, followed by acidification.
[0047] In a preferred embodiment (V) is dissolved in methanol (generally 2 to 100 equivalents based on (V)), and base is added (generally 3 to 100 equivalents). In a preferred embodiment water is added, preferably 5 to 200% by weight based on the base. The base is preferably selected from NaOH, KOH, NaOCH3 and KOCH3, NaOH, particularly as a 50% by weight aqueous solution, is especially preferred.
[0048] The reaction temperature is generally in the range of from about 20 to about 120°C, preferably about 40 to about 90°C. The reaction is generally carried out at ambient pressure or elevated pressure. The reaction time is generally from 1 to 8 h, preferably from 1 to 5 h.
[0049] Working up and isolation of compound (XII) can be achieved by standard measures. Compound (XII) can be treated with a dehydrating agent, such as acetic anhydride, to form the anhydride (XIII),
[0050] Anhydride (XIII) can be converted to herbicidal imidazolinones (VII) in analogy to the conversion of compound (V). Preparation of compounds (VII) by a respective process is a further embodiment illustrated. According to this embodiment a process is provided for preparing a herbicidal imidazolinone compound of formula (VII), above comprising the steps of: (i)/(ii)/(iii)/(iv) preparing a compound of formula (V) as described above, (v-a) reacting compound (V) in methanol with MOH or MOCH3, where M is an alkali metal cation, followed by acidification, to form compound (XII)
where Z, Z1 are as in formula (I), and (ν-β) treating compound (XII) with a dehydrating agent to form anhydride (XIII),
(XIII) where Z, Z1 are as in formula (II), and either (v-ya1) reacting anhydride (XIII) with aminonitrile (IX),
(IX) where R4 and R5 are as in formula (VII), to obtain nitrile compound (XIV),
(XIV)
where the symbols are as in formula (VII), (v-ya2) hydrolyzing the nitrile group in compound (XIV) to obtain amide (XV),
(XV) where the symbols are as in formula (VII), or (v-yb) reacting anhydride (XIII) with an amino carboxamide (VIII)
(VIII) where R4 and R5 are as in formula (VII), to obtain amide (XV), and (vi-α) condensation of amide (XV) to yield a herbicidal imidazolinone (VII).
[0051] The invention is illustrated by the following examples without limiting it thereby. Examples
Reference Example 1 5-(Hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl/methyl ester (mixture) [0052] 50 g (0.24 mol) MPDC-DME (5-methyl-pyridine-2,3-dicarboxylic acid dimethyl ester (lla)) were mixed at -45°C with 27.1 g (0.26 mol) n-BuONO in 750 ml DMF. Afterwards 25.1 g (0.36 mol) KOMe were added in portions at the same temperature, the mixture was stirred for 2 h at the same temperature, and subsequently added to a mixture of ice water (2500 ml) and concentrated HCI (250 ml). The resulting mixture was extracted three times with 200 ml methyl tert.-butyl ether (MTBE), the combined organic phases were washed once with water and once with saturated brine, dried over magnesium sulphate, and the organic solvent was subsequently removed in vacuo. 41.7 g of an about 1:1 mixture of 5-(hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester were obtained, having a 90% purity (1H-NMR). Yield: 67%. 1H-NMR (CDCI3):0.95 ppm (m, 6H, CH3), 1.45 ppm (m, 4H, CH2), 1.75 ppm (m, 4H, CH2), 3.95 ppm (s, 2H, OCH3), 4.0 ppm (m, 2H, OCH2), 4.05 ppm (s, 2H, OCH3), 4.4 ppm (m, 2H, OCH2), 8.2 ppm (s, 2H, 2x CH), 8.35 ppm (s, 2H, 2x CH), 8.95 ppm (s, 2H, 2x CH=N).
Reference Example 2 5-(Hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester (mixture) [0053] 20 g (0.1 mol) MPDC-DME were mixed at-10°Cwith 10.8 g (0.11 mol) n-BuONO in 30 ml DMF. Afterwards 7.7 g (0.14 mol) NaOMe were added in portions at the same temperature, the mixture was stirred for 0.5 h at the same temperature, and subsequently added to a mixture of ice water (1000 ml) and concentrated HCI (100 ml). The resulting mixture was extracted three times with 100 ml MTBE, the combined organic phases were washed once with water and once with saturated brine, dried over magnesium sulphate, and the organic solvent was subsequently removed in vacuo. 18.1 g of an about 1:1 mixture of 5-(hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester were obtained, having a 90% purity (1H-NMR). Yield: 72%.
Reference Example 3 5-(Hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester (mixture) [0054] 20 g (0.1 mol) MPDC-DME were mixed at 0°C with 10.8 g (0.11 mol) n-BuONO in 30 ml DMF. Afterwards 7.7 g (0.14 mol) NaOMe were added in portions at the same temperature, the mixture was stirred for 0.5 h at the same temperature, and subsequently added to a mixture of ice water (1000 ml) and concentrated HCI (100 ml). The resulting mixture was extracted three times with 100 ml MTBE, the combined organic phases were washed once with water and once with saturated brine, dried over magnesium sulphate, and the organic solvent was subsequently removed in vacuo. 19.5 g of an about 1:1 mixture of 5-(hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester were obtained, having a 90% purity (1H-NMR). Yield: 78%.
Reference Example 4 5-(Hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester (mixture) [0055] 20 g (0.1 mol) MPDC-DME were mixed at 20°C with 10,8 g (0.11 mol) n-BuONO in 30 ml DMF. Afterwards 7.7 g (0.14 mol) NaOMe were added in portions at the same temperature, the mixture was stirred for 0.5 h at the same temperature, and subsequently added to a mixture of ice water (1000 ml) and concentrated HCI (100 ml). The resulting mixture was extracted three times with 100 ml MTBE, the combined organic phases were washed once with water and once with saturated brine, dried over magnesium sulphate, and the organic solvent was subsequently removed in vacuo. 16.0 g of an about 1:1 mixture of 5-(hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester were obtained, having a 95% purity (1H-NMR). Yield: 68%.
Reference Example 5 5-Formyl-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester (mixture) [0056] 41.2 g (0.17 mol) of a 5-(hydroxyiminomethyl)-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester mixture were stirred in 252 g 5 percent aqueous hydrochloric acid with 58.2 g (1.9 mol) paraformaldehyde at 60°C for 2 h. After cooling the mixture was extracted three times with 100 ml dichloromethane, the combined organic phases were washed once with water and once with saturated brine, dried over magnesium sulphate, and the organic solvent was subsequently removed in vacuo. 36.6 g of a 90 percent mixture (about 1:1) of 5-formyl-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester were obtained. Yield: 86%. 1H-NMR (CDCI3):0.95 ppm (m, 6H, CH3), 1.45 ppm (m, 4H, CH2), 1.75 ppm (m, 4H, CH2), 4.0 ppm (s, 2H, OCH3), 4.05 ppm (s, 2H, OCH3), 4.4 ppm (m, 2H, OCH2), 4.45 ppm (m, 2H, OCH2l), 8.7 ppm (s, 2H, 2x CH), 9.25 ppm (s, 2H, 2x CH), 10.2 ppm (s, 2H, 2x CHO).
Reference Example 6 5-Formyl-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester (mixture) (One-Pot-Procedure) [0057] 20 g (0.1 mol) MPDC-DME were mixed at 0°C with 10.8 g (0.11 mol) n-BuONO in 30 ml DMF. Afterwards 7.7 g (0.14 mol) NaOMe were added in portions at the same temperature, the mixture was stirred for 0.5 h at the same temperature, and subsequently stirred at 0°C to 244 g 5 percent aqueous HCI. 31.6 g (1.5 mol) paraformaldehyde were added, and the mixture was stirred at 60°C for 2 h. After cooling the mixture was extracted three times with 100 ml dichloromethane, the combined organic phases were washed once with water and once with saturated brine, dried over magnesium sulphate, and the organic solvent was subsequently removed in vacuo. 16.6 g of a 82 percent mixture (about 1:1) of 5-formyl-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester were obtained. Yield: 64%.
Example 1 5-Hydroxymethyl-pyridine-2,3-dicarboxylic acid [0058] 10 g (0.04 mol) of a 90 percent 5-formyl-pyridine-2,3-dicarboxylic acid butyl ester/methyl ester mixture were added at 0°C to a solution of technical grade sodium borohydride (Sigma-Aldrich) in 100 ml water, and stirred for 1 h at this temperature. Afterwards the pH-value was adjusted to 2 with 2N HCI under cooling, the water was evaporated in vacuo, and the residue was twice dried aceotropically with 100 ml toluene. The isolated product still contains salt and is 30 percent according to 1H-/13C-NMR. Yield: 85%. 1H-NMR (DMSO-d6):4.65 ppm (s, 2H, CH2), 6.6 ppm (s, 1H, OH), 8.35 ppm (s, 1H, CH), 8.75 ppm (s, 1H, CH).
Reference Example 7 5-Chloromethyl-pyridine-2,3-dicarboxylic acid anhydride (3-chloromethyl-furo[3,4-b]pyridine-5,7-dione) (Va) [0059] 5 g (0.008 mol) 5-hydroxymethyl-pyridine-2,3-dicarboxylic acid (30 percent) were dissolved in 20 ml toluene and heated to reflux. Subsequently 9.1 g (0.08 mol) thionylchloride were added. After 3 h at reflux the reaction mixture was evaporated to dryness in vacuo, the residue was twice dried aceotropically with 40 ml toluene, taken up in 40 ml hot toluene, and the toluene was distilled off in vacuo. 0.8 g 5-chloromethyl-pyridine-2,3-dicarboxylic acid anhydride were obtained in a purity of 90% (1H-NMR). Yield: 48%. 1H-NMR (CDCI3):4.8 ppm (s, 2H, CH2), 8.45 ppm (s, 1H, CH) 9.2 ppm (s, 1H, CH).
Reference Example 8 Synthesis of imazamox (Vila) (a) Synthesis of carbonitrile (Xla) [0060]
[0061] 9.6 g (48 mmol) anhydride (Va), 40.0 g (435 mmol) toluene and 6.7 g (112 mmol) acetic acid were charged to a reactor and heated up to 69°C. 7.2 g (51 mmol) a-amino-1,2-dimethyl butyronitrile (Va) were added over 25 min at a temperature between 72°C and 76°C. The mixture was stirred for additional 90 min at 75°C. After cooling the mixture was directly used in the next stage. (b) Synthesis of 2-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-5-chloromethyl nicotinic acid (Xa) [0062]
[0063] To 14.9 g (48 mmol) nitirile (XI) (from stage (a)), 6.0 g (59 mmol) sulfuric acid (98%) was added at 69°C to 80°C within 5 min. 4.1 g (228 mmol) water was added at 70°C to 78°C and stirring continued at 69°C for 5 h. The emerging product forms a toluene insoluble oil. The reaction mixture was used without working up in the following stage. (c) Synthesis of imazamox (Vila) [0064]
[0065] To 15.7 g (48 mmol) amido compound (Xa) (reaction mixture from stage (b)) 94 g (2.94 mol) methanol was added at 65°C and subsequently 42 g (525 mmol) NaOH (50% in water). The solution turned into a suspension, and stirring was continued for additional 90 min.
[0066] 80 g water was added and solvents were removed at 50°C and 80-8 mbar. Residue was dissolved in water and the basic solution acidified with 29 g sulfuric acid (98%). Imazamox precipitated from pH 4 on. The suspension was filtered at room temperature and washed with 100 ml water.
Yield: 16.5 g (82% pure, 44 mmol, 92%)
Purity was enhanced to > 95% (HPLC) by stirring the crude product with water.
Reference Example 9
Synthesis of 5-methoxymethyl-pyridine-2,3-dicarboxylic acid (Xlla) [0067]
[0068] 7.0 g (35 mmol) 5-chloromethyl-pyridine-2,3-dicarboxylic acid anhydride (Va) were dissolved in 165 g (5.16 mol) methanol at room temperature, causing formation of monoesters. 14 g (350 mmol) NaOH (50% in water) were slowly added whereupon the temperature rose to 50°C and carboxylate started to precipitate. Stirring was continued for additional 5 h at 65°C.
[0069] The solvents were then removed in vacuo, and the solid residue was dissolved in 53 g water and acidified with 19 g sulfuric acid (98%) up to pH = 1.5. The aqueous solution was extracted three times with 90 g THF at 40°C and the combined organic phases were concentrated to dryness.
Yield: 7.4 g (32 mmol, 90%)
REFERENCES CITED IN THE DESCRIPTION
This list of references cited by the applicant is for the reader's convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.
Patent documents cited in the description • EP0322616A Γ00031 fPOOSl f00291 [00411 • F.PQ74736QA [00031 • EP0933362A Γ00031 • US5334576A |0007] • ER0„3„22,8,f M2 .[QflflZl • US5026859A Γ08081 • US4562257A [00341 • EP0144595A Γ00461
Non-patent literature cited in the description • Q. Bl et al.Modern Agrochemicals, 2007, vol. 6, 210-14 [00031 . Heterocycles, 1992, vol. 34, 1605- |00661 • C. GUÉRET et al.J. Labelled Cpd. Radiopharm, 2001, [00081
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| US12095708P | 2008-12-09 | 2008-12-09 | |
| EP09764528.7A EP2376472B1 (en) | 2008-12-09 | 2009-12-07 | Process for manufacturing 5-formyl-pyridine-2,3-dicarboxylic acid esters |
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| US (1) | US8629279B2 (en) |
| EP (2) | EP2376472B1 (en) |
| JP (1) | JP5570524B2 (en) |
| CN (1) | CN102245591B (en) |
| BR (1) | BRPI0923219A2 (en) |
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| US8722893B2 (en) * | 2008-11-13 | 2014-05-13 | Basf Se | Process for manufacturing 5-chloromethyl-2,3-pyridine dicarboxylic acid anhydrides |
| MX2020002370A (en) | 2018-12-29 | 2020-10-12 | Huawei Tech Co Ltd | Light splitting apparatus. |
| CN112142713A (en) * | 2019-06-27 | 2020-12-29 | 山东润博生物科技有限公司 | Synthesis method of imazethapyr |
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| FR2537580B1 (en) * | 1982-12-13 | 1985-09-20 | Rhone Poulenc Agrochimie | NOVEL BENZYLCARBAMOYLPYRIDINE DERIVATIVES, PROCESSES FOR THEIR PREPARATION AND THEIR USE AS HERBICIDES FOR WEEDING CROPS |
| DE3330604A1 (en) | 1983-08-25 | 1985-03-28 | Hoechst Ag, 6230 Frankfurt | Process for the preparation of bromomethylthiophenecarboxylic acid esters |
| US4562257A (en) | 1983-11-07 | 1985-12-31 | American Cyanamid Company | Preparation of substituted and unsubstituted 2-carbamoyl nicotinic and 3-quinolinecarboxylic acids |
| US4782157A (en) | 1984-12-03 | 1988-11-01 | American Cyanamid Co. | Preparation of substituted and unsubstituted 2-carbamoyl nicotinic and 3-quinolinecarboxylic acids |
| JPH07611B2 (en) * | 1986-01-24 | 1995-01-11 | 日産化学工業株式会社 | Pyridine derivative, method for producing the same, and herbicide |
| GB2192877A (en) * | 1986-07-22 | 1988-01-27 | Shell Int Research | Herbicidal imidazolinyl compounds |
| US5334576A (en) | 1986-07-28 | 1994-08-02 | American Cyanamid Company | 5 (and/or 6) substituted 2-(2-imidazolin-2-yl)nicotinic acids, esters and salts, useful as herbicidal agents and novel intermediates for the preparation of said nicotinic acids, esters and salts |
| EP0322616A3 (en) | 1987-12-31 | 1989-10-18 | American Cyanamid Company | Novel 5(and/or 6)substituted 2-(2-imidazolin-2-yl)nicotinic acids, esters and salts, useful as herbicidal agents and nivel intermediates for the preparation of said nicotinic acids, esters and salts |
| US5026859A (en) | 1989-12-27 | 1991-06-25 | American Cyanamid Company | Alkyl esters of 5-heterocyclic-pyridine-2,3-dicarboxylic acids |
| US5215568A (en) | 1991-10-31 | 1993-06-01 | American Cyanamid Company | Oxime derivatives of formylpyridyl imidazolinones, the herbicidal use and methods for the preparation thereof |
| US5288866A (en) | 1991-12-20 | 1994-02-22 | American Cyanamid Company | 5,6-disubstituted-3-pyridylmethyl ammonium halide compounds useful for the preparation of 5- (substituted methyl)-2,3-pyridinedicarboxylic acids |
| ATE205831T1 (en) | 1995-06-05 | 2001-10-15 | Basf Ag | IMPROVED METHOD FOR PRODUCING 5-(ALKOXYMETHYL)-PYRIDINE-2,3-DICARBOXYLATE SALT |
| US5892050A (en) | 1998-01-28 | 1999-04-06 | American Cyanamid Company | Process for the preparation of pyridine dicarboxylate derivatives |
| WO2010051654A1 (en) * | 2008-11-05 | 2010-05-14 | Google Inc. | Custom language models |
| CN101739539B (en) * | 2008-11-06 | 2011-09-21 | 国民技术股份有限公司 | Method for resisting car reading conflict by automatic frequency hopping |
| WO2010055042A1 (en) | 2008-11-13 | 2010-05-20 | Basf Se | 2-[(1-cyanopropyl)carbamoyl]-5-methoxymethyl nicotinic acids and the use thereof in manufacturing herbicidal imidazolinones |
| RU2549896C2 (en) | 2008-11-13 | 2015-05-10 | Басф Се | Method for producing substituted 3-pyridylmethyl ammonium bromides |
| CN102245577B (en) | 2008-11-13 | 2014-03-26 | 巴斯夫欧洲公司 | 2-[(1-cyanopropyl)carbamoyl]-5-chloromethyl nicotinic acids and the use thereof in manufacturing herbicidal imidazolinones |
| DE102008043921A1 (en) | 2008-11-20 | 2010-05-27 | Robert Bosch Gmbh | Device for electrical cell voltage measurements |
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| ES2670677T3 (en) | 2018-05-31 |
| US20110245505A1 (en) | 2011-10-06 |
| IL241806B (en) | 2018-05-31 |
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| EP2376472A1 (en) | 2011-10-19 |
| JP5570524B2 (en) | 2014-08-13 |
| WO2010066668A1 (en) | 2010-06-17 |
| US8629279B2 (en) | 2014-01-14 |
| IL241806A0 (en) | 2015-11-30 |
| CN102245591A (en) | 2011-11-16 |
| IL213144A0 (en) | 2011-07-31 |
| EP2982673B1 (en) | 2018-02-21 |
| BRPI0923219A2 (en) | 2020-08-11 |
| JP2012511508A (en) | 2012-05-24 |
| IL213144A (en) | 2015-11-30 |
| CN102245591B (en) | 2014-12-03 |
| EP2376472B1 (en) | 2015-08-19 |
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